ABSTRACT: Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the United States. Two important risk factors for CRC are a history of chronic colitis or inflammatory bowel disease (IBD) and obesity, both of which are increasing at an alarming rate worldwide. However, the mechanisms linking these diseases to CRC are not well understood and thus there is a pressing need to define them. The NLR (NOD-like receptor or NBD-LRR) is a multi-member gene family that encodes a group of cytosolic proteins that are involved in the intracellular sensing of microbial products as well as damage-associated molecular patterns. NOD2, an NLR family member, has a strong genetic association with Crohns' disease and has been implicated in colitis-associated CRC (CAC). Additionally, NLRs including NOD2 and NLRP6 can affect the microbiome to impact colitis in mice, suggesting that family members are important in maintaining or disrupting the homeostasis of gut microbiome. We and others have shown a role for the inflammasome in models of IBD and CRC. This group of proteins respond to pathogen derived products and can assemble into inflammasomes in conjunction with the key NLR adaptor protein, ASC (apoptotic speck containing protein with a CARD) to activate the IL-1? and IL-18-processing enzyme caspase-1. Caspase-1 activation then leads to the cleavage and maturation of pro-IL-1beta and IL-18. In addition to the analyses of these well-studied inflammasome components in models of IBD and CRC, we and others have shown a strong role for other NLRs which have anti- inflammatory functions (referred to as regulatory NLRs), and can attenuate the clinical outcome in animal models of colitis and inflammation-associated colon carcinoma. Furthermore, recent findings in our lab showed that these regulatory NLRs play a protective role in spontaneous CRC in a genetic model of colon cancer. This proposal plans to examine the roles of inflammasome and regulatory NLRs in human and murine models of gastrointestinal cancer.